Volume 17 - Issue 20 - p 1,23–23 doi: 10.1097/01.NT.0000526677.81786.42
Researchers reported evidence suggesting that treatment with an asthma drug was associated with a steep decline in risk for development of Parkinson's disease in a population-wide prescription database from Norway. They offered molecular evidence that beta2-adrenoreceptors are linked to transcription of alpha-synuclein, and may therefore be a potential target for therapies.
The common asthma drug salbutamol (also called albuterol) reduces expression of alpha-synuclein, the protein at the core of Lewy bodies in Parkinson's disease (PD), and improves neuronal survival in several preclinical models. What's more, and potentially more important for the human disease, treatment with salbutamol was associated with a steep decline in risk for development of PD in a population-wide prescription database from Norway.
“These findings are exciting and potentially have important implications for neuroprotection in Parkinson's disease,” said Anthony E. Lang, MD, FAAN, professor of neurology and director of the Program in Parkinson's Disease at the University of Toronto, who was not involved in the study, which was published in the September 1 issue of Science.
Clearance of misfolded alpha-synuclein has been the focus of much work in PD, but until this paper, no group has reported a search for compounds that would reduce its production.
“We hypothesized that this would be the most direct solution,” said principal investigator Clemens R. Scherzer, MD, associate professor of neurology at Harvard Medical School and Brigham & Women's Hospital in Boston.
That such down-regulation might be possible was suggested by previous discoveries by Dr. Scherzer's group, when they identified multiple transcription factors that directly control the gene. “This suggested a gene-regulatory path for lowering alpha-synuclein and inspired our gene expression drug screen in the current work,” he said.
STUDY DESIGN
To conduct that screen, the researchers exposed neuroblastoma cells to more than one thousand compounds, including natural products and Food and Drug Administration (FDA)-approved drugs, looking for those that reduced production of alpha-synuclein. After a multi-stage replication process, four compounds emerged, three of which — salbutamol, clenbuterol, and metaproterenol — are beta2-adrenoreceptor agonists. All three are prescribed for asthma. Salbutamol and metaproterenol are approved by the FDA, while clenbuterol is not, but it is prescribed in Europe. Intriguingly, the fourth compound was riluzole, approved for treatment of amyotrophic lateral sclerosis.
Each of the three beta2-adrenoreceptor agonists reduced alpha-synuclein protein expression in a dose-dependent manner to about 75 percent of normal in the cell-based screen. In mice, 24 hours of treatment with clenbuterol lowered alpha-synuclein production in the substantia nigra. And in patient cells from individuals with an alpha-synuclein triplication, clenbuterol treatment also reduced protein production.
The team found molecular evidence suggesting that treatment with clenbuterol decreased histone acetylation at sites regulating transcription of the alpha-synuclein gene, a change that would be likely to reduce transcription factor access to the gene, which may account for the reduced production of the protein.
Further supporting a direct role for the beta2-adrenoreceptor in regulating alpha-synuclein production, the team found that knocking out the gene for the receptor, and thus preventing it from signaling at all, more than doubled alpha-synuclein levels in neurons.
“Thus, beta2-adrenoreceptors are linked to transcription of alpha-synuclein,” Dr. Scherzer said, and may therefore be a potential target for therapies.
To test that hypothesis in humans, he and his team turned to the Norwegian Prescription Database, which contains complete information on prescriptions for the 4.6 million residents of the country, beginning in 2004. Over six years of follow-up, the proportion of people not developing PD was highest among those who had received salbutamol for at least 180 days during follow-up (n=69,511), was intermediate among those who had received it for between 60 and 180 days (72,911), and was lowest among those receiving it for less than 60 days, or never. Taking all salbutamol users together, the rate ratio was 0.66, with a 95% confidence interval of 0.58 to 0.76.
One possible link between asthma treatment and reduced PD risk might be smoking, Dr. Scherzer said, which is a behavior known to both increase asthma and reduce the likelihood of developing PD. But if the observed risk reduction were explained by a link through smoking, one would expect other asthma drugs, such as inhaled corticosteroids, which don't act through the beta2-adrenergic receptor, to also be associated with reduced PD risk. This was not the case, he said, “so it is unlikely smoking can fully account for this association.”
Based on these findings, Dr. Scherzer said it was logical to begin thinking about a clinical trial of a beta2-adrenergic receptor agonist to determine if it can slow development of PD after diagnosis. However, he cautioned, “there is reason to rethink the paradigm of how clinical trials are traditionally designed and conducted for PD,” noting the consistent failure of treatments intended for disease modification in recent decades.
Dr. Scherzer turned up another surprising result in the population study, strengthening the conclusion that beta2-adrenergic receptor signaling influences development of PD. He found that exposure to propranolol, which blocks this receptor, markedly increased PD risk, with a rate ratio of 2.2 (95% CI 1.62 to 3.00). Back in the lab, his team showed that propranolol increased histone acetylation near the alpha-synuclein gene, increased protein production, and abrogated clenbuterol's ability to lower alpha-synuclein levels.
“Our data raise the concern that propranolol might increase the risk of Parkinson's disease, and that is worrisome,” Dr. Scherzer said. “At the same time, it's too early to draw firm conclusions for clinical practice. More research and replication in other populations is warranted to clarify this question.”
EXPERT COMMENTARY
“This is a pretty well-investigated area, so the discovery of a receptor of this type that regulates alpha-synuclein is surprising,” said Steven Finkbeiner, MD, PhD, director of the Taube/Koret Center for Neurodegenerative Disease and Gladstone Institutes and professor in the departments of neurology and physiology at the University of California, San Francisco, who was not involved with the study.
“Although the effect in cell models is modest, it is possible that this might be sufficient to produce a meaningful effect on Parkinson's risk, based on what we know about the effects of gene duplication and triplication and non-coding variants,” Dr. Finkbeiner said. “And the rate ratio reduction to 0.66 in the treatment cohort compared to the untreated one is potentially quite remarkable.”
But there are important unanswered questions, Dr. Finkbeiner added. The proposed mechanism, through modification of histone acetylation, “suggests that the drug is probably regulating many genes. Is modest reduction in alpha-synuclein responsible for the effects or are other targets even more important?”
Dr. Lang of Toronto added: “The concept of screening compounds that reduce transcription of the alpha-synuclein gene is novel, and the preclinical science looks very strong. The finding that propranolol has an opposite effect is very interesting and complies with the hypothesis very nicely.”
But the real importance of the paper comes from the epidemiologic data, Dr. Lang said. “We have failed to develop effective treatments with our toxin models of PD, and now we have models that over-express alpha-synuclein, and there are likely to be a lot of failures from these as well.” The difference here is that the benefits seen in the preclinical work seem to also be operating in a large human population, he said, adding: “But that needs to be confirmed in other databases.”
The Norwegian data raise several important questions that will need to be addressed as well, he said. “The effect of salbutamol appears to be rapid and quite profound. If that's the case, why haven't we seen this in epidemiological studies before?”
Regarding the propranolol effect on PD risk, he noted that propranolol is also used in PD to treat postural and action tremor. “But we never see the other features of the disease get worse,” which might be expected if the drug can increase alpha-synuclein production strongly enough to dramatically increase PD risk. “Why aren't we seeing propranolol worsening pre-existing Parkinson's disease?”
“I think the basic science here is really compelling, and it moves us in a completely new direction,” Dr. Lang said. “But the epidemiology is really where most people will look before taking this into clinical trials. That would be one of the more important things to reproduce as quickly as possible.”
http://journals.lww.com/neurotodayonline/Fulltext/2017/10190/In_the_Pipeline_Parkinson_s_Disease__Why_a_Common.1.aspx
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